12alpha-lower alkyl steroids and their method of preparation



United States Patent ce 3,143,559

Patented Aug. 4, 1964 or together R and R is keto, and R is lower alkyl(pref- 3,143,559 erably methyl). Hon-LOWER L YL TE AND THEIR These newsteroids of this invention are prepared by WTHGD 0F PREPARATIONinteracting a 3,20-diketal of 9a-fluoro-1l-ketoprogester- Gordon H.Thomas, Birmingham, England, and Josef 5 Fried, Princeton, N.J.,assignors to Olin Mathieson Chemical Corporation, New York, N.Y., acorporation one or 9a-fiuoro-A -pregnadiene-3,11,20-trione with lithiumlower alkyl (e.g., lithium methyl), thereby yielding of Virginia the3,20-diketal of IZa-methyl-ll-ketoprogesterone and No Drawing. Filed0ct.3, i962, Ser.No. 223,000 of 12-methyl-al't-pregnadiems,1llotlionerespec- 4 Cl i (Cl, 260-39745) tively. The resulting IZa-methyl diketalcan then be hydrolyzed in the usual manner to give the free Hut-methyl-This application is a continuation-in-part of our apll-ketoprogesteroneor lZea-methyl-A -pregnadiene-3,l1, plication, Serial No. 847,459, filedOctober 20, 1959, now ZO-trione; or reduced to yield the correspondingll-hyabandoned, which in turn is a continuation-in-part of our droxyderivative. If the reduction is carried out with a application, SerialNo. 696,904, filed November 18, 1957, reducing agent such as lithiumaluminum hydride, the now abandoned. 15 3,20-diketal ofl2oc-methyl-1lB-hydroxyprogesterone (or This invention relates to thesynthesis of steroids, and of 12ix-methyl-A-pregnadiene-1lB-ol-3,20-dione) is obhas for its object the provision ofa new class of physitained as the major product. If, on the other hand,the ologically active steroids, which may be represented by reduction isdone by means of a reducing agent such as the formula lithium metal inliquid ammonia, the 3,20-diketal of IZa-methyl-llu-hydroxyprogesterone(or of IZa-methyl- (3H3 A -pregnadienella-ol-3,2O-dione) is recovered.Both 1 0:0 of these ll-hydroxy derivatives can then be hydrolyzed in R lthe usual manner to yield the respective 3,20-diketone derivative. Theresulting 12oz-II16thYl-1luc-hYdIOXY-PIO- R gesterone (or 1Za-methyI-A-pregnadiene-1la-ol,3,20-dione) can then, if desired, be acylated in theusual man- 2 1 ner, as by treatment with the acid anhydride or acyl Jlalide of the desired acid, to yield the corresponding 11oz- 0= acyloxyderivative.

This series of steps is illustrated by the following equawherein the1,2-position is saturated or double-bonded, tions wherein9a-fluoro-1l-ketoprogesterone 3,20-bis- R is hydrogen, R is a-hydroxy,a-acyloxy, or fi-hydroxy, ethylene ketal is employed as the startingmaterial:

W I! I1 tizQU ti; r

VII. R"=CH, VIII. R"=CZH As suitable starting materials for the processof this invention may be mentioned any 3,20-diketal of9a-fluoro-ll-ketoprogesterone or of 9a-flu0ro-A -pregnadiene-3,11,20-trione, as exemplified by the diketals with 1,2 or 1,3-dihydricalcohols such as ethylene glycol and propylene glycol. These starting3,20-diketals can be prepared in the usual manner from 9a-fluoroll-ketoprogesterone and 9a-fluoro-A -pregnadiene-B,11,20-trione,respectively, by treating the 3,20-dione with, for example, a dihydricalcohol, such as ethylene glycol and propylene glycol, in the presenceof an acid catalyst. These ketals are then interacted with lithium loweralkyl (e.g., lithium methyl and lithium ethyl), preferably in an organicsolvent for the steroid, such as benzene, the reaction being conductedat any normal temperature, such as ambient temperature. The reactionresults in a mixture of two products, one of which is the desireddiketal of 12amethyl-ll-ketoprogesterone (or of l2a-methyl-A-pregnadiene-3,ll,20-trione), and the other is a diketal ofllamethyl-9B,llB-oxidoprogesterone (or of 11a-methyl-9B, llfi 0xido-A-pregnadiene-3,20-dione). The products can then be separated byfractional crystallization.

The l2a-rnethyl-ll-ketoprogesterone diketal (or 12ozmethyl-A-pregnadiene-S,11,20-trione diketal) formed can then be hydrolyzed inthe usual manner, as by treatment with a dilute aqueous acid at anelevated temperature, to yield the corresponding free 3,11,20-triketonederivatives.

The IZa-methyl-ll-ketoprogesterone diketal, or its correspondingl-dehydro analogue, can also be reduced to the corresponding ll-hydroxyderivative. If this reduction is done by means of a complex metalhydride, such as lithium aluminum hydride or lithium borohydride,preferably at an elevated temperature in an inert organic solvent (e.g.,tetrahydrofuran), the corresponding lLB-hydroxy derivatives are formed(e.g., IZOc-HIClIhYl-llfi-hY- droxyprogesterone 3,20-diketal and12a-methyl-A -pregnadiene-llB-ol-3,20-dione 3,20-diketal), which in turncan be hydrolyzed as described hereinbefore to the free 3,20-diketonederivatives.

If, however, the reduction is carried out by means of an alkali metal(e.g., lithium) in liquid ammonia, then the lla-hydroxy derivatives(e.g., lZa-methyl-lla-hydroxyprogesterone 3,20-diketal and 12a-methyl-A-pregnadiene 11oz ol-3,20-dione 3,20-diketal) are formed. Thesella-hydroxy steroids can also be hydrolyzed to the free 3,20-diketonederivatives as described hereinbefore, or they can be acylated, in theusual manner, by treatment with an acyl halide or acid anhydride of thedesired acid. Particularly preferred are the acyl chlorides or acidanhydrides of hydrocarbon carboxylic acid having less than ten carbonatoms, as exemplified by the lower alkanoic acids (e.g., acetic,propionic, and enan-thic acid), the monocyclic aromatic carboxylic acids(e.g., benzoic and toluic acid), the monocyclic aralkanoic acids (e.g.,phenacetic and ,B-phenylpropionic acid), the lower alkenoic acids, thecycloalkane carboxylic acids, and the cycloalkene carboxylic acids. Theacylation is preferably conducted in the presence of an organic base,such as pyridine.

The steroids of this invention wherein free keto groups are present inthe 3 and 20 positions are physiologically active substances whichpossess progestational activity. Hence the steroids of this inventioncan be used in lieu of known progestational steroids, such asprogesterone, in the treatment of habitual abortion, being formulatedfor such administration in the same type of peroral preparations asprogesterone, for example, with concentration and/ or dosage based onthe activity of the particular compound. Moreover, it has surprisinglybeen found that those compounds of this invention are many more timesmore active than are the corresponding lZ-unsubstituted derivatives.Thus, whereas lla-hydroxyprogesterone possesses only 4 the activity ofprogesterone, 12amethyl-lla-hydroxyprogesterone is As as active aprogestational steroid; and, whereas, llfl-hydroxyprogesterone possessesonly 4 the activity of progesterone, 12amethyl-11 fi-hydroxyprogesteroneis twice as active as progesterone. In addition the steroids of thisinvention are useful intermediates in the preparation of thecorresponding 9a-hal0 steroid derivatives by the general methoddescribed in US. Patent No. 2,852,511.

The following examples are illustrative of the invention (alltemperatures being in centigrade):

EXAMPLE 1 l 2 a-M ethyl-1 1 -Ket0pr0gester0ne 3 ,ZO-B is- Ethylene Ketal(I) (0 PREPARATION OF FLUORO 11 KETOPROGES- TERONE 3,20-BIS-ETHYLENEKETAL A mixture of 10 g. of 9cc-fluoro-ll-ketoprogesterone, 350 ml. ofbenzene, 80 ml. of ethylene glycol and 200 mg. of para-toluene-sulfonicacid monohydrate is refluxed with stirring for 72 hours. The reactionmixture is then cooled to room temperature and neutralized with sodiumbicarbonate solution. The phases are separated and the aqueous layerreextracted with additional amounts of benzene. The combined benzeneextracts are washed with water, dried over sodium sulfate and evaporatedto dryness in vacuo. The crude residue on crystallization fromacetone-hexane yields about 11 g. of the essentially pure bis-ethyleneketal melting at about l79l82. Recrystallization of this material frommethanol gives an analytical sample of the following properties: M.P.about 189190; -25.

Analysis.-Calcd. for C H O F (434.53): C, 69.10; H, 8.12. Found: C,69.19; H, 8.18.

(b) PREPARATION OF 12aMETHYL-11-KETOPROGES- TERONE 3,20-BIS-ETHYLENEKETAL A solution of 9a-fluoro-ll-ketoprogesterone 3,20-bisethylene ketal(10 g.) in benzene ml.) is treated with an ethereal solution of lithiummethyl ml., 13.5 mg. of lithium metal/ml) The solution is stirred for 4hours at room temperature and then the excess lithium methyl isdecomposed by the addition of ice. Chloroform (300 ml.) is added, andthe mixture is washed several times with water, dried over sodiumsulfate and evaporated in vacuo. Trituration of the residue with hexanegives about 4.2 g. of l2a-methyl-1l-ketoprogesterone 3,

ZO-bis-ethylene ketal (I), M.P. about 135-138". A second crop ofcrystals (about 2.4 g., MP. about 124-130") is obtained on concentratingthe hexane mother liquor. Crystallization from methanol gives ananalytical sample melting at about 139142, [aJ 8.8 (c. 0.716 in CHCl5.87 1 Analysis.Calcd. for C H O (430.56): C, 72.50; H, 8.90. Found: C,72.71; H, 8.90.

EXAMPLE 2 J Zea-1E4 ethyl-1 1 -Ketprogesterone 3,20-Bis- Ethylene Ketal(I) $32 no absorption in the hydroxyl or carbonyl region.

Analysis.Calcd. for C H O (430.56): C, 72.50; H, 8.90. Found: C, 72.32;H, 8.64.

Similarly, by substituting an equivalent amount of lithium ethyl for thelithium methyl in the procedures of Examples 1 and 2,12a-ethyl-1l-ketoprogesterone 3,20- bis-ethylene ketal (ll) is obtained.Furthermore, any diketal may be substituted for the 3,20-bis-ethyleneketal in the procedures of Examples 1 and 2, thereby yielding thecorresponding 3,20-diketal derivative.

EXAMPLE 3 12ez-Mezhyl-A -Pregnadiene-iJZ ,ZO-TriOne 3,20-Bis-EthyleneKetal By substituting an equal amount of 9a-fluoro-A-pregnadiene-3,11,20-trione for the steroid reactant in the proceduresof Examples 1 and 2, 12u-methyl-A -pregnadiene-3,11,20-trione3,20-bis-ethy1ene ketal is obtained.

EXAMPLE 4 J 2 oz-M ethyl-1 1 -Kezoprogester0ne (III) A solution of 300mg. of l2a-methyl-ll-ketoprogesterone 3,20-bis-ethylene ketal in 10 ml.methanol and 1 ml. of 8% sulfuric acid is heated under reflux for 4hours. The mixture is then diluted with water, the precipitated solid(about 201 mg, M.P. about 154156) collected and crystallized fromacetone-hexane. The resulting sample of 12a-methyl-1l-ketoprogesteronemelts at about 155-157; [[1] +227 (c. 1.36 in CHClg);

A212? 236 my (15,800); k113i? 5.88, 5.96, 6.18;;

Analysis.-Calcd. for C l-1 0 (342.46): C, 77.15; H, 8.83. Found: C,76.60; H, 8.76.

Similarly, by substituting 12a-ethyl-1l-ketoprogesterone3,20-bis-ethylene ketal for the 12a-methyl steroid in the procedure ofExample 4, 12a-ethyl-1l-ketoprogesterone (IV) is obtained. Furthermore,any other bis ketal derivative can be similarly hydrolyzed to yield thesame free 3,11,20-triketone derivatives.

EXAMPLE 5 12a Methyl-1],B-Hydroxyprogesterone 3,20-Bz's-Ethylene Ketal(V) and IZec-MethyZ-ZJa-Hydroxyprogesterone 3,20-Bz's-Ethylene Ketal(IX) A solution of 1 g. of IZa-methyl-l l-ketoprogesterone3,20-bis-ethylene ketal in 50 ml. of dry tetrahydrofuran is heated underreflux with 1 g. of lithium aluminum hydride for 18 hours. Ice is addedto the cooled solution to decompose excess reagent and then a saturatedaqueous solution of sodium sulfate is added with stirring until theprecipitated aluminum salts are formed into a slurry. The clear ethersolution is decanted off and the inorganic material is washed twice withchloroform. The combined organic extracts are dried over sodium sulfateand then evaporated in vacuo. The residue is dissolved in 10 ml. benzeneand absorbed on a column of 30 g. of alumina. Elution with benzene (900ml.) and chloroform-benzene (1:9, 500 ml.), followed by crystallizationfrom acetonehexane, yields 12a-methyl-l lfi-hydroxyprogesterone 3,20-bis-ethylene ketal (V) (about 660 mg.) melting at about 169-175Crystallization from acetone-hexane affords an analytical sample whichmelts at about 177-179"; [aJ 11.5 (c. 1.24 in CHClg);

Analysis.Calcd. for C H O (432.58): C, 72.19; H, 9.32. Found: C, 72.30;H, 9.20.

Elution of the column with chloroform-benzene (4:1, 400 ml.), followedby crystallization from acetone-hexane, yieldsIZa-methyl-lla-hydroxyprogesterone 3,20-bisethylene ketal (1X) (about 30mg), M.P. about 204- 206. Two crystallizations from acetone-hexane givesa sample which melts at about 209-210; [a] 26.7 (c. 1.02 in CHCIAnalysis.Calcd. for C H O (432.58): C, 72.19; H, 9.32. Found: C, 72.47;H, 9.20.

Similarly, by substituting 1 g. of 12a-ethyl-11-ketoprogesterone3,20-bis-ethylene ketal or IZa-methyl-A -Pregnadiene-3,11,20-tri one3,20-bis-ethylene ketal for the 12::- methyl-ll-ketoprogesterone3,20-bis-ethylene ketal in the procedure of Example 5,12a-ethyl-11B-hydroxyprogesterone 3,20-bis-ethylene ketal (V1) and12a-6ihYl-1la-hY- droxyprogesterone 3,20-bis-ethylene ketal (X); and 12-methyl-A -pregnadiene-11,8-ol-3,20-dione 3,20-bis-ethylene ketal and12amethy1-A -pregnadiene-11a-ol-3,20-dione 3,20-bis-ethylene ketal areobtained respectively.

EXAMPLE 6 1 2 a-M ethyl-l J cz-H ydroxy progesterone 3,20-Bis- EthyleneKetal (D() To a stirred solution of 12a-methyl-1l-ketoprogesterone3,20-bis-ethylene ketal (640 mg.) in ml. of liquid ammonia and 20 ml. ofmethanol, is added 500 mg. of lithium in small pieces over 15 minutes.The liquid ammonia is allowed to evaporate at room temperature and theresidue is diluted with 50 ml. of water. The precipitated solid (about620 mg., M.P. about 193-207) is collected, Washed well with water anddried. Crystallization from methanol gives an analytical sample of thellot-hydroxy compound (IX) which meltsat about 211- 213; [111 28.5 (c.1.13 in CHCl The identity of this sample ofIZa-methyl-llu-hydroxyprogesterone 3,20- bis-ethylene ketal with thatobtained in Example 5 is established by mixture melting pointdetermination and comparison of infrared spectrum.

EXAMPLE 7 1 Zea-M ethyl-1 1 ,B-H ydroxy progesterone (VII) CHCI3); N 241111,. (16,600); Alla? max.

2.9, 5.91 (inflection); 5.95,

Anaylsis.-Calcd. for C H O (344.48): C, 76.70; H, 9.32. Found: C, 76.59;H, 9.41.

Similarly, 12a-ethyl-1lp-hydroxyprogesterone 3,20-bisethylene ketal and12a-methyl-A -pregnadiene-l15-01- 3,20-dione 3,20-bis-ethylene ketal canbe hydrolyzed to IZa-ethyl-llfi-hydroxyprogesterone (VIII) and12a-methyl-A -pregnadiene-11fl-ol-3,20-dione, respectively.

EXAMPLE 8 12 a-Methyl-Z 1 oc-H ydroxy progesterone (XI) A solution of193 mg. of 12a-methyl-1lea-hydroxyprogesterone 3,20-bis-ethylene ketalin 5 ml. of methanol and 1 ml. of 8% sulfuric acid is heated underreflux for one hour. Dilution with water gives about 147 mg. of 12amethyl-1lu-hydroxyprogesterone which melts at about 207211.Crystallization from methanol yields a pure sample having melting point215-218; [041 +155 (c. 1.02 in CHClg);

A22? 241 mp. (15,700); REEL? 2.95, 5.92, 5.99, 6.22

Analysis.-Ca1cd. for C H O (344.48): C, 76.70; H, 9.36. Found: C, 76.50;H, 9.23.

Similarly, 12e-ethyl lla-hydroxyprogesterone 3,20- bis-ethylene ketaland 1Za-methyl-A -pregnadiene-1la-ol- 3,20-dione 3,20-bis-ethylene ketalcan be hydrolyzed to 12a-ethyl-1lahydroxyprogesterone and 12OL-I[1tl1y1A pregnadiene-l1a-ol-3,20-dione, respectively.

EXAMPLE 9 1 2 cc-M ethyl-1 1 oc-H ydroxy progesterone 11 a-A cetate(XII) A solution of 50 mg. of 12a-methyl-1la-hydroxyprogesterone in 1ml. of pyridine and 0.3 ml. of acetic anhydride is heated at 80 for 3hours. The mixture is then diluted with iced water, the precipitatecollected, washed with Water and dried in vacuo. Two crystallizationsfrom acetone-hexane gives about 33 mg. of the Ila-acetate (XII) havingM.P. about 191193; [a] +159 (c. 1.05 in CHCI kg; 239 my (14,700); k312i?5.80, 5.90, 5.98, 6.20, 8.05.

Analysis.-Calcd. for C H O (386.51): C, 74.57; H, 8.87. Found: C, 74.98;H, 8.96.

Similarly, by substituting other acylating agents for the aceticanhydride in the procedure of Example 9, the corresponding acyloxyderivatives are formed. Thus, propionic anhydride and benzoyl chlorideyield the Ila-propionate and lla-benzoate, respectively. Furthermore, if12a-ethyl-1loc-hydroxyprogesterone and 12a-methyl-Apregnadiene-11a-ol-3,20-dione is substituted for the12amethyl-llu-hydroxyprogesterone in the procedure of EX- ample 9, thecorresponding respective Ila-acetates are obtained.

The invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

1. A compound selected from the group consisting of steroids of theformula wherein R is hydrogen, R is fi-hydroxy, and R is lower alkyl.

2. 12a-methyl-1lii-hydroxyprogesterone.

3. A process for preparing a steroid selected from the group consistingof l2oc-(1OW61 alkyl)-11-ketoprogesterone 3,20-diketal and 12a-(loWeralkylA -pregnadiene- 3,11,20-trione 3,20-diketal, which comprisesinteracting a steroid selected from the group consisting of9a-fluO1'0-1lketoprogesterone 3,20-diketal and 9a-fluoro-A-pregnadiene-3,11,20-trione 3,20-diketal with lithium lower alkyl andrecovering the IZrz-lOWBI alkyl steroid formed.

4. The process of claim 3 wherein the lithium reactant is lithiummethyl.

References Cited in the file of this patent UNITED STATES PATENTS2,702,291 Sondheimer et al Feb. 15, 1955 FOREIGN PATENTS 739,597 GreatBritain Nov. 2, 1955

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDS OF THEFORMULA